Impact of Time to First Epinephrine Administration on Outcomes After In-Hospital Cardiac Arrest With Initial Nonshockable Rhythm

Précis

This study found no significant difference in the sustained return of spontaneous circulation or survival to hospital discharge based on the timing of the first epinephrine administration in these patients.

Objective

Image credit: Quality Stock Arts | stock.adobe.com

The primary objective was to evaluate the impact of time to first epinephrine administration on sustained return of spontaneous circulation (ROSC) in initial nonshockable rhythms. The secondary objective was survival to hospital discharge.

Study Design

This was a retrospective, multicenter, institutional review board–approved chart review evaluating adult patients with initial nonshockable rhythm after in-hospital cardiac arrest from July 1, 2020, to June 30, 2023.

Methods

Patients 18 years and older with initial nonshockable, in-hospital cardiac arrest were included. Patients were excluded if they experienced cardiac arrest prior to hospital arrival or transitioned to hospice within 24 hours of ROSC. Patients were analyzed based on timing of the first epinephrine administration (< 2 minutes and ≥ 2 minutes) upon identification of cardiac arrest. The χ2 test was used to compare the primary and secondary outcomes between groups.

Conclusion

The results did not demonstrate a difference between timing of the first epinephrine administration on sustained ROSC in initial nonshockable rhythms

Introduction

Cardiac arrest occurs when there is cessation of cardiac mechanical activity confirmed by signs of absence of circulation, such as no pulse and unresponsiveness. Out-ofhospital cardiac arrest is more common than in-hospital arrest; however, survival rates to discharge are higher in patients who experience in-hospital cardiac arrest.¹ The incidence of in-hospital cardiac arrest in the United States is approximately 10 per 1000 hospital admissions.¹ Survival-to-discharge rates are substantially higher in patients with an initial shockable rhythm—reported at 2 to 3 times higher than initial nonshockable rhythm.² Nonshockable rhythms are often the initial rhythms (approximately 80% of cases) noted for in-hospital cardiac arrest; however, with the introduction of rapid response teams in the hospital setting, mortality has decreased.^1,2 Nonshockable rhythms include pulseless electrical activity (PEA) and asystole. The most common causes of in-hospital cardiac arrest are hypoxia, acute coronary syndrome, arrhythmias, and hypovolemia.^1,3

Epinephrine administration concurrently with high-quality cardiopulmonary resuscitation (CPR) improves survival in patients with nonshockable rhythms.³ Epinephrine, a sympathomimetic catecholamine, acts on both α- and β-adrenergic receptors. Epinephrine causes vasoconstriction through its potent effect on α-adrenergic receptors. The beneficial effects of epinephrine are thought to be due to α-adrenergic properties, resulting in increased coronary and cerebral perfusion pressure. The American Heart Association (AHA) guidelines for CPR recommend that epinephrine be dosed at 1 mg intravenously every 3 to 5 minutes, with the first administration as soon as possible.³

Limited data are available for the optimal time to administer epinephrine in patients with nonshockable rhythms. The information that is available suggests that earlier administration of epinephrine in hospitalized patients with nonshockable cardiac arrest is associated with a higher probability of ROSC; however, no exact time frame has been established.⁴

In 2014, Donnino et al published a retrospective analysis aiming to determine whether earlier administration of epinephrine in patients with in-hospital, nonshockable cardiac arrest was associated with increased ROSC, survival, and neurologically intact survival. The findings demonstrated a significant stepwise decrease in in-hospital survival with each minute that epinephrine was delayed. When time to administration was analyzed in 3-minute intervals, they also found a significant decrease in in-hospital survival with each increasing interval.⁴

In 2021, Bakhsh et al published a retrospective analysis comparing immediate intravenous (IV) epinephrine (defined as administration within 1 minute after recognition of cardiac arrest) to early IV epinephrine (defined as administration 2 minutes or longer after recognition) in patients with in-hospital, nonshockable cardiac arrest. A total of 360 patients were included in the analysis, and sustained ROSC was achieved in 95 patients. Immediate administration of epinephrine compared with early administration was associated with statistically higher rates of sustained ROSC (15.3% vs 11.1%; P = .04).⁵

The results from these prior studies indicate further research is needed to correlate early administration of epinephrine in nonshockable rhythms with clinical outcomes, such as sustained ROSC and survival to hospital discharge. The current practice within the facilities included in this study is to administer epinephrine within the first 5 minutes of a nonshockable rhythm, in alignment with AHA’s Get With the Guidelines–Resuscitation (GWTG-R).⁶ To date, study facilities have not routinely tracked more immediate epinephrine administration times and utilize epinephrine administration within 5 minutes as the reporting metric in nonshockable rhythms.

The purpose of this study was to compare time to first epinephrine administration with outcomes in patients with in-hospital cardiac arrest with initial nonshockable rhythms. The primary objective was to evaluate the time to first epinephrine administration (< 2 minutes or ≥ 2 minutes) on sustained ROSC 24 hours after in-hospital cardiac arrest in initial nonshockable rhythms. The secondary objective was survival to hospital discharge.

Methods

This was a retrospective, multicenter, institutional review board–approved chart review evaluating adult patients with in-hospital cardiac arrest from July 1, 2020, to June 30, 2023. Data were obtained from 3 facilities within a 19-hospital community health system. Patients were included if they were 18 years or older, experienced the first cardiac arrest after arriving at the hospital, had an initial nonshockable rhythm, and had the code narrator utilized for chart documentation. Patients were excluded if cardiac arrest occurred prior to arrival at the hospital or in the operating room, they were pregnant, or they were transitioned to hospice within 24 hours of ROSC. Patients in the emergency department were included if their first cardiac arrest was after arrival. Time to epinephrine administration was defined as the interval in minutes from recognition of loss of pulse to the first epinephrine administration. Patients were categorized into groups based on those with first epinephrine administration in less than 2 minutes and those with epinephrine administration at 2 minutes or longer from recognition of cardiac arrest. Patients were identified utilizing a data report of patients with code blue documentation in the code narrator. The code narrator is built into the electronic medical record and allows for documentation of time of each event/intervention, respiratory status, heart rate, blood pressure, cardiac rhythm, defibrillation/cardioversion (if applicable), and medication administration. Data were collected from chart documentation in the code narrator function of the electronic medical record.

Within the practice setting, personnel are trained to activate the code blue team and immediately initiate CPR upon recognition of cardiac arrest. The code blue team may include a house supervisor, physician, pharmacist, respiratory therapist, chaplain, and phlebotomist as well as rapid response nurses. Code blue team members are certified in advanced cardiac life support. Documentation of the code is performed via the code narrator. The code narrator documentation is available to be completed in real time but may also be transcribed retrospectively; both methods are instituted within the study facilities.

Descriptive statistics were used to assess the baseline characteristics. The χ2 test was used to compare baseline characteristics for nominal data, and the Mann-Whitney U test was used to compare nonparametric numerical data. The χ² test also was used to compare the primary outcome of sustained ROSC and the secondary outcome of survival to discharge. A P value less than .05 was considered significant.

We ran logistic regression models analyzing the impact of potential confounding variables with time to first epinephrine administration, initial rhythm (PEA and asystole), and CPR duration on sustained ROSC and survival to discharge. The confidence intervals were set to 95%.

Results

We reviewed 173 patients for inclusion in the study (Figure) and included 100 patients with initial nonshockable rhythms. Baseline characteristics are shown in the Table. There were significant differences in baseline characteristics for rhythm type and median CPR duration. The median time to first epinephrine administration was 1 minute (IQR, 1-2 minutes), and median CPR duration was 8 minutes (IQR, 4-15 minutes). Sustained ROSC was achieved in 29 patients (29%). Survival to hospital discharge occurred in 9 patients (9%).

Epinephrine was first administered in less than 2 minutes to 66 patients (66%) and at 2 minutes or longer to 34 patients (34%). There was no difference in the ROSC achieved in patients who received epinephrine at under 2 minutes and those who received epinephrine at 2 minutes or longer (47 [71%] vs 23 [68%]; P = .71). There was no difference in sustained ROSC at 24 hours or longer in patients who received epinephrine in less than 2 minutes vs those who received epinephrine at 2 minutes or longer (19 [40%] vs 10 [43%], respectively; P = .95) or in survival to discharge (7 [11%] vs 2 [6%]; P = .43).

After adjusting for covariates, initial rhythm, and CPR duration, we found no association between time to first epinephrine administration and incidence of sustained ROSC at 24 hours or longer or survival to discharge. The same regression model showed no association between initial rhythm of PEA or asystole on incidence of sustained ROSC at 24 hours or longer or survival to discharge. There also was no association of duration of CPR with incidence of sustained ROSC at 24 hours or longer; however, duration of CPR had an independent effect on survival to discharge. Every 1-minute increase in duration of CPR decreased the odds of survival to discharge by 26% (OR, 0.74; 95% CI, 0.55-0.99; P = .04).

In a subgroup analysis of 32 patients with COVID-19, median time to epinephrine administration was 1 minute (IQR, 1-2 minutes) and 12 patients achieved sustained ROSC (38%). Epinephrine was administered in less than 2 minutes to 22 patients (69%) and at 2 minutes or longer to 10 patients (31%). Sustained ROSC was similar in patients who received epinephrine in less than 2 minutes compared with those who received epinephrine at 2 minutes or longer (36% vs 40%, respectively). No patients with COVID-19 survived to discharge.

CPR, cardiopulmonary resuscitation; IQR, interquartile range; PEA, pulseless electrical activity.

*Patients categorized in multiple diagnosis categories, if applicable

Discussion

The AHA recommends administration of epinephrine as soon as possible upon recognition of cardiac arrest and repeating it every 3 to 5 minutes.³ Our study demonstrated the attainability of immediate epinephrine administration, with a median epinephrine administration time of 1 minute (IQR, 1-2 minutes).

The results of this study showed no difference in sustained ROSC with epinephrine administration in less than 2 minutes vs at 2 minutes or longer. Conversely, in a previous retrospective study, Bakhsh et al⁵ demonstrated an association between earlier epinephrine administration and increased sustained ROSC for 24 hours.

Overall survival to discharge of 9% was lower than the GWTG-R survival to discharge of approximately 25% in nonshockable, in-hospital cardiac arrest.³ Survival to discharge was numerically higher in the group that received epinephrine in less than 2 minutes compared with the group that received it at 2 minutes or longer, although this result was not significant.

Potential confounders shown in previous studies to impact outcomes include duration of CPR, intubation during CPR, and initial rhythm (PEA vs asystole).^2,7-9 Baseline characteristics of this study showed a difference in median duration of CPR and initial rhythm between groups. Previous literature suggests that an initial rhythm of PEA is associated with improved prognosis compared with asystole.^7,8 There was a greater proportion of patients with PEA than asystole in the group who received epinephrine in less than 2 minutes and a greater proportion of patients with asystole than PEA in the group who received epinephrine at 2 minutes or longer. A logistic regression showed no association between initial rhythm of PEA, initial rhythm of asystole, duration of CPR, or time to first epinephrine administration on sustained ROSC as well as no association between initial rhythm of PEA, initial rhythm of asystole, or time to first epinephrine administration on survival to discharge; however, an increase in duration of CPR independently decreased the odds of survival to discharge.

Study limitations

Limitations of this study include the retrospective nature, small sample size, unmeasured confounders (such as intubation during CPR, nature of chart documentation, inclusion of patients with unknown initial rhythms), and inability to assess delivery of high-quality CPR.

Insertion of an endotracheal tube may interfere with early administration of epinephrine; however, data on intubation during CPR was not collected or assessed. Data collection relied upon chart documentation in the code narrator. Often the code narrator is not documented in real time, which could lead to possible transcription errors. In addition, inability to assess high-quality CPR affects generalizability of results.

Moreover, patients with COVID-19 were not excluded from analysis. Thirty-two percent of patients tested positive for COVID-19 during their hospital admission. A similar proportion of patients in both comparator groups had COVID-19. Previous literature suggests an approximate 1.5% survival-to-discharge rate after in-hospital cardiac arrest in patients with COVID-19.¹⁰ In a post hoc subgroup analysis, no patients with COVID-19 survived to discharge in this study, which could have contributed to the overall lower-than-expected survival to discharge. Due to isolation precautions for patients with COVID-19, there is a theoretical delayed time to epinephrine administration, which was not demonstrated in this study as patients with COVID-19 had a median time to epinephrine administration of 1 minute (IQR, 1-2 minutes).

Conclusion

Although these results demonstrate the attainability of early epinephrine administration within 1 minute of recognition of loss of pulse, they did not demonstrate an association between timing of epinephrine administration on sustained ROSC in patients with initial nonshockable rhythms. Larger studies with more robust design are needed to assess the effects of time to epinephrine administration on sustained ROSC and survival to discharge.

REFERENCES

1. Penketh J, Nolan JP. In-hospital cardiac arrest: the state of the art. Crit Care. 2022;26(1):376. doi:10.1186/s13054-022-04247-y

2. Andersen LW, Holmberg MJ, Berg KM, Donnino MW, Granfeldt A. In-hospital cardiac arrest: a review. JAMA. 2019;321(12):1200-1210. doi:10.1001/jama.2019.1696

3. Panchal AR, Bartos JA, Cabañas JG, et al; Adult Basic and Advanced Life Support Writing Group. Part 3: adult basic and advanced life support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(suppl 2):S366-S468. doi:10.1161/CIR.0000000000000916

4. Donnino MW, Salciccioli JD, Howell MD, et al; American Heart Association’s Get With The Guidelines-Resuscitation Investigators. Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry. BMJ. 2014;348:g3028. doi:10.1136/bmj.g3028

5. Bakhsh A, Safhi M, Alghamdi A, et al. Immediate intravenous epinephrine versus early intravenous epinephrine for in-hospital cardiopulmonary arrest. BMC Anesthesiol. 2021;21(1):147. doi:10.1186/s12871-021-01346-1

6. Get With the Guidelines - Resuscitation. American Heart Association. Accessed March 5, 2025. https://www.heart.org/en/professional/quality-improvement/get-with-the-guidelines/get-with-the-guidelines-resuscitation

7. Nolan JP, Soar J, Smith GB, et al; National Cardiac Arrest Audit. Incidence and outcome of in-hospital cardiac arrest in the United Kingdom National Cardiac Arrest Audit. Resuscitation. 2014;85(8):987-992. doi:10.1016/j.resuscitation.2014.04.002

8. Meaney PA, Nadkarni VM, Kern KB, Indik JH, Halperin HR, Berg RA. Rhythms and outcomes of adult in-hospital cardiac arrest. Crit Care Med. 2010;38(1):101-108. doi:10.1097/CCM.0b013e3181b43282

9. Andersen LW, Granfeldt A, Callaway CW, et al; American Heart Association’s Get With The Guidelines-Resuscitation Investigators. Association between tracheal intubation during adult in-hospital cardiac arrest and survival. JAMA. 2017;317(5):494-506. doi:10.1001/jama.2016.20165

10. Aldabagh M, Wagle S, Cesa M, Yu A, Farooq M, Goldberg Y. Survival of in-hospital cardiac arrest in COVID-19 infected patients. Healthcare (Basel). 2021;9(10):1315. doi:10.3390/healthcare9101315